title: Germinal center kinase-like kinase overexpression in T cells as a novel biomarker in rheumatoid arthritis.
abstract: OBJECTIVE
  Germinal center kinase-like kinase (GLK; also called MAPKKKK-3) activates protein kinase Cθ (PKCθ) during T cell activation and controls autoimmunity in lupus patients. Intracellular kinases are involved in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine the role of GLK in RA.
  
  
  METHODS
  The severity of collagen-induced arthritis (CIA) was studied in GLK-deficient mice. Expression levels of GLK from RA patients were determined by Western blotting, flow cytometry, real-time polymerase chain reaction, and immunohistochemical staining. Localization of GLK in T cells was identified by confocal microscopy. RA disease activity was assessed using the Disease Activity Score in 28 joints.
  
  
  RESULTS
  GLK-deficient mice displayed impaired CIA development and decreased inflammatory cytokine levels. Local T cell infiltration and collagen restimulation responses were impaired by GLK deficiency. RA patients showed significantly higher GLK protein and messenger RNA levels in peripheral blood T cells than did healthy controls. GLK-overexpressing T cells in synovial fluid and synovial tissue samples from RA patients were increased compared with those from osteoarthritis patients. Confocal microscopy and flow cytometry showed that GLK colocalized and coexisted with phosphorylated PKCθ in T cells from RA patients. Frequencies of GLK-expressing T cells were significantly correlated with RA disease activity.
  
  
  CONCLUSIONS
  GLK overexpression in T cells contributes to the pathogenesis of RA, indicating that GLK is a novel biomarker for autoimmune disease severity and a potential therapeutic target for RA.
authors.affiliation: Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China, and National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Huai-Chia
authors.initials: HC
authors.lastname: Chuang
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Lin
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Tsai
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Wu
authors.forename: Ning-Rong
authors.initials: NR
authors.lastname: Gong
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hung
authors.forename: Tsuo-Hung
authors.initials: TH
authors.lastname: Lan
authors.forename: Joung-Liang
authors.initials: JL
authors.lastname: Lan
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
authors.forename: Der-Yuan
authors.initials: DY
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001169:Arthritis, Experimental / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D017252:CD3 Complex; D011494:Protein Kinases; C108114:GCK-like kinase